DESCRIPTION: (Applicant's Abstract) Repeated exposure to drugs of abuse produces specific neuroadaptations in the mesolimbic dopamine system that could alter the reinforcing properties of drugs and/or increase the propensity to relapse. One type of neuroadaptation involves changes in the levels of specific glutamate receptor subunits in the ventral segmental area (VTA). In contrast, extinction from cocaine self-administration produces a context specific change in the levels of specific glutamate receptor subunits in the shell region of the nucleus accumbens (NAc). Many drug-related neuroadaptations may result from alterations in cAMP-Response Element Binding protein (CREB)-mediated gene regulation during drug taking and withdrawal. The proposed studies will further characterize neuroadaptations produced by drug self-administration, withdrawal, and extinction from drug self-administration. In addition, the role of these neuroadaptations in drug reward and propensity to relapse will be tested directly by genetically altering levels of these target proteins in vivo with viral-mediated gene transfer techniques. These animals will then be tested in behavioral paradigms designed to measure changes in drug reward and the propensity to relapse. Parallel biochemical experiments will measure viral-mediated changes in glutamate receptor subunits in an attempt to correlate temporally both biochemical and behavioral changes.